Process for producing optically active ethly (3r, 5s, 6e)-7- [2-cycloproply-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate

ABSTRACT

The objective of this invention is to provide a process for producing an optically active isomer of ethyl 7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate by optically resolving an optical isomer mixture of the compound at a high productivity. The process is characterized by employing a filler comprising a carrier and a specific amount of cellulose tris (4-chlorophenyl carbamate) supported the carrier and carrying out chromatographic separation under the condition that the capacity factors have specific values.

TECHNICAL FIELD

The present invention relates to a process for producing opticallyactive ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate.More particularly, the present invention relates to a process that canproduce with high productivity optically active ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate,an intermediate product for calcium^(I) bis{(3R, 5S,6E)-7-(2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate,which is effective in the prevention and treatment of hyperlipemia,arterial sclerosis, etc.

BACKGROUND ART

As commonly known, optically isomers usually have different actions onliving bodies, in spite of the fact that they are chemically the samecompound. Therefore in the fields of medicine, pharmacy and industriesrelating to biochemistry, to prepare optically pure compounds has becomea very important subject to improve the efficacy of a medicine for aunit dosage and to prevent damage by side effects of the medicine.

Optically active statins are very effective in the prevention andtreatment of hyperlipemia, arterial sclerosis, etc. For example,WO95/23125 publication discloses an industrial process for producingoptically active statins.

However, with a conventional optical resolution filler that included10-20 wt % of an active compound, the productivity was low. Consequentlyhas been strongly desired a process for producing optically activestatins, which process is more excellent in the separation productivity.

The present invention was made in the aforementioned circumstances. Theobjective of this invention is to provide a process for producingoptically active statins, especially optically active ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoatewith higher separation productivity.

DISCLOSURE OF THE INVENTION

In order to solve the aforementioned problem, the present inventionprovides a process for producing optically active ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoatewhich comprises separating an optical isomer mixture of ethyl7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-hepteno-ate by a simulated moving bed chromatography employing a filler forliquid chromatography comprising a carrier and a cellulosetris(4-chlorophenyl carbamate) supported on the carrier wherein theamount of the cellulose tris(4-chlorophenyl carbamate) is at least 23weight % based on the total weight of the carrier and the cellulose tris(4-chlorophenyl carbamate) under the condition that capacity factors k1′and/or k2′ is at least 1, the capacity factors being calculated by thefollowing formulae:k1′=(v1−v0)/v0, andk2′=(v2−v0)/v0wherein v1 and v2 each are the respective retention volumes of theoptical isomers, which are the solutes, and v0 is the dead volume.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration that shows an example of a simulatedmoving bed chromatographic separation apparatus employed in thisinvention. In this figure, reference numerals 1-12 denote unit columns,reference numeral 13 denotes an eluent supply conduit, reference numeral14 an extract draw-out conduit, reference numeral 15 an opticalisomer-mixture supply conduit, reference numeral 16 a raffinate draw-outconduit, reference numeral 17 a circulation conduit, and referencenumeral 18 a circulation pump.

FIG. 2 is a schematic illustration that shows another example of asimulated moving bed chromatographic separation apparatus employed inthis invention.

FIG. 3 is a chromatogram obtained in Working Example 1.

FIG. 4 is a chromatogram obtained in Working Example 2.

FIG. 5 is a chromatogram obtained in Comparative Example 1.

FIG. 6 is a chromatogram obtained in Comparative Example 2.

FIG. 7 is a chromatogram obtained in Comparative Example 3.

DETAILED DESCRIPTION OF THE INVENTION

Preferred Embodiments of the invention will be explained in detail inthe followings.

The present invention employs a special filler comprising a carrier anda specific amount of a cellulose tris(4-chloro-phenyl carbamate)supported on the carrier, as filler for liquid chromatography.

The number average polymerization degree, which is indicated by anaverage number of pyranose or furanose rings per molecule, of thiscellulose tris (4-chlorophenyl carbamate) is typically at least 5,preferably not less than 10. This degree does not have specific upperlimits. In view of ease in handling, however, it should be not more than1000, preferably not more than 500. If we dare mention a preferablerange of the number average polymerization degree ranges, it may bebetween 5 and 1000, more preferably between 10 and 500.

The degree of substitution with 4-chlorophenyl carbamate groups in thecellulose tris(4-chlorophenyl carbamate) is usually 10%-100%, preferably30%-100% and more preferably 80%-100%. A degree of less than 10% is notpreferable because the resulting polymer has little ability of opticalresolution. Also, a degree of less than 30% is not very preferablebecause optical resolution is sometimes insufficient depending upon thespecies and concentration of the optical isomer mixture to be separated.On the other hand, a degree in excess of 80% is preferable becauseparticles for the filler having excellent optical resolution ability canbe obtained. The degree can be determined by elemental analysis ofcarbon, hydrogen and nitrogen before and after the substitution.

For the carrier can be used organic and inorganic porous substances. Theinorganic porous substances are preferable. Examples of the suitableorganic carriers are a high molecular weight compound selected from thegroup consisting of polystyrene, polyacrylamide, polyacrylate, etc.Examples of the suitable inorganic carriers are silica gel, alumina,magnesia, zirconia, glass, kaolin, titanium oxide, silicate salts,hydroxyapatite, etc. The especially preferable carrier is silica gel.The particle size of silica gel usually ranges between 0.μm and 10 mm,preferably between 1 μm and 300 μm. The average pore size of silica gelis 10 Å-100 μm, preferably 50 Å-50,000 Å. The surface of the carriershould be treated to remove the remaining silanol that has undesirableeffects on the surface. However, if the surface is not treated at all,it will not cause problems.

The amount of the cellulose tris(4-chlorophenyl carbamate) supported onthe carrier is preferably at least 23 weight % based on the total weightof the cellulose tris(4-chlorophenyl carbamate) and the carrier. Fromthe viewpoint of productivity, the amount is preferably 27 weight %,particularly preferably 27-60 weight %. The amount has no specific upperlimit. However, when the amount exceeds 60 weight %, the number of theplates is lowered, which undesirably results in low efficiency in theoptical separation.

The filler for liquid chromatography may be prepared either through adirect bonding of the cellulose tris(4-chlorophenyl carbamate) with thecarrier, or through coating the carrier with a solution including thecellulose tris(4-chlorophenyl carbamate) and removing the solvent bydistillation. The solvent may be any organic solvent that is commonlyused, as long as it can dissolve the cellulose tris(4-chlorophenylcarbamate).

Moreover, by forming further chemical bonds between the carrier and theapplied cellulose tris(4-chlorophenyl carbamate), and between themolecules of the cellulose tris(4-chlorophenyl carbamate) itself on thecarrier, the compound may be firmly fixed on the carrier. The furtherchemical bonds may be formed through reactions by utilizing anothercomponent, by irradiating the compound on the carrier with light,radiant rays such as γ ray or electromagnetic waves such as micro wave,or by forming radicals with a free-radical initiator.

The optically active compounds that can be produced by the method inaccordance with this invention include ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoaterepresented by the following formula (I).

In the process of this invention, an optical isomer mixture of ethyl7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoateis subjected to optical resolution by a simulated moving bedchromatography employing a super critical liquid or an ordinary solventfor the mobile phase. The ordinary solvent is particularly suitable forthe mobile phase of this invention. An example of the simulated movingbed chromatographic separation method will be given in the followings.It should be noted that the separation method in accordance with theinvention is not limited to the example and that the conditionsincluding the cycle time may be set at the operator's discretion foroptimizing the operation, as disclosed by, e.g. WO 00/25885.

Separation through adsorption by a simulated moving bed chromatographyis effected by continuously carrying out an adsorption step, aconcentration step, a desorption step and an eluent recovery step incirculation.

(1) Adsorption Step

An optical isomer mixture solution is contacted with a filler, wherebyan optically active isomer easily adsorbed by the filler (stronglyadsorbable substance) is adsorbed by the filler while the other opticalisomer not easily adsorbed by the filler (poorly adsorbable substance)goes into raffinate, which is recovered together with the eluent.

(2) Concentration Step

The filler, which has adsorbed the strongly adsorbable substance, iscontacted with a portion of extract as will be described below, thepoorly adsorbable substance retained on the filler is expelled, and thusthe adsorbable substance is concentrated.

(3) Desorption Step

The filler, which has the concentrated strongly adsorbable substance iscontacted with the eluent, and the substance is expelled from the fillerand taken out of the simulated moving bed apparatus together with theeluent as extract.

(4) Eluent Recovery Step

The filler that contains substantially only the eluent is contacted witha portion of the raffinate, and a portion of the eluent contained in thefiller is recovered as an eluent recovery.

Now the procedures are explained in detail with reference to theattached drawings. FIG. 1 is a schematic illustration that shows anexample of the simulated moving bed apparatus employed in thisinvention. FIG. 2 is a schematic illustration that shows another exampleof the simulated moving bed apparatus employed in this invention.

In FIG. 1, the beds, which are the main part of the simulated moving bedapparatus, are divided into 12 (twelve) unit columns. In FIG. 2, theapparatus has 8 (eight) unit columns. The number of the unit columns andthe size of each unit column are not limited to the above-mentioned, butdecided depending on the factors such as the composition and flow rateof the optical isomer mixture solution, and the pressure loss and thedimensions of the apparatus.

In FIG. 1, unit columns 1-12 are filled with a filler and they aremutually connected with fluid passages. The eluent is introduced througheluent supply conduit 13, the extract is taken out through extractconduit 14, the mixture solution containing optical isomers is suppliedvia conduit 15, the raffinate is taken out through raffinate conduit 16,and the fluid is recirculated through recirculation conduit 17 by meansof pump 18.

In the state of unit columns 1-12 and conduits 13-16 as shown in FIG. 1,desorption is done in unit columns 1-3, concentration in unit columns4-6, adsorption in unit columns 7-9, and eluent recovery in unit columns10-12. In the simulated moving bed system like this, the workingpositions of the respective supply conduits and the respectivetaking-out conduits are shifted one unit column by one unit column inthe fluid flow direction at a constant time interval by operation ofvalves. In the next stage, therefore, desorption is done in unit columns2-4, concentration in unit columns 5-7, adsorption in unit columns 8-10,and eluent recovery in unit columns 11-1. By repeating this operationsuccessively, each step is carried out in a set of unit columns that areshifted one column by one column. Thus optical resolution of an opticalisomer mixture is efficiently achieved.

In the state of unit columns 1-8 and conduits 13-16 as shown in FIG. 2,eluent recovery is done in unit column 1, adsorption in unit columns2-5, concentration in unit columns 6-7, and desorption in unit column 8.In the simulated moving bed system like this, the working positions ofthe respective supply conduits and the respective taking-out conduitsare shifted one unit column by one unit column in the fluid flowdirection at a constant time interval by operation of valves. In thenext stage, therefore, desorption is done in unit column 2,concentration in unit columns 3-6, adsorption in unit columns 7-8, andeluent recovery in unit column 1. By repeating this operationsuccessively, each step is carried out in a set of unit columns that areshifted one column by one column. Thus optical resolution of an opticalisomer mixture is efficiently achieved.

In the simulated moving bed chromatography in accordance with thisinvention, the chromatographic separation should be carried out underthe condition that capacity factors k1′ and/or k2′ is at least 1. Inthis specification “k1′” and “k2′” mean the capacity factors calculatedby the following formulae:k1′=(v1−v0)/v0   (1)k2′=(v2−v0)/v0   (2)wherein each of v1 and v2 is the retention volume of each opticalisomer, which is an eluted component, and v0 is a dead volume.

When both of capacity factors k1′ and k2′ are less than 1, theproductivity is lowered, which is undesirable. Either of k1′ and k2′should be at least 1. From the viewpoint of improving productivity, morepreferable is that both of the factors are at least 1.

EXAMPLES Synthesizing Example 1 Preparation of an HPLC Column Containinga Filler that Includes 24 Weight % of Cellulosetris(4-chlorophenyl-carbamate)

(1) Surface Treatment of Silica Gel

A porous silica gel (the average particle size: 20 μm) was subjected toan aminopropyl silane treatment (APS treatment) through a reaction ofthe silica gel with 3-aminopropyl triethoxy silane by a known method.Reaction of the obtained APS-treated silica gel with 3,5-dimethyl phenylisocyanate produced a carbamoyl-surface-treated silica gel.

(2) Synthesis of Cellulose tris(4-chlorophenyl carbamate)

Under nitrogen atmosphere, 100 g of cellulose and 714.1 g (2.5equivalent weight) of 4-chlorophenyl carbamate in 3.8 liters of driedpyridine were heated and stirred for 60 hours at the reflux temperatureof pyridine. The solution was poured into 40 liters of 2-propanol. Theformed precipitate was isolated by filtration with a glass filter,washed several times with 2-propanl, and then vacuum-dried at 800° C.for 15 hours. The collected was a yellowish white solid product, whichweighed 287 g. The yield was 75%.

(3) Preparation of a Filler Made of Silica Gel Supporting 24 Weight % ofCellulose tris(4-chlorophenyl carbamate)

120 g of cellulose tris(4-chlorophenyl carbamate) obtained in step (2)above was dissolved in 600 ml of acetone. 380 g of the treated silicagel prepared in step (1) above was uniformly coated with the half amountof this polymer solution. The acetone was vacuum-distilled off from thecoated silica gel at 40° C. for 45 minutes under 40 kPa. The silica gelwas again coated with the remaining half of the polymer solution, andacetone was vacuum-distilled off in the same way. Then, the aimed fillermade of silica gel supporting 24 weight % of cellulosetris(4-chlorophenyl carbamate) was obtained.

(4) Preparation of a Filled HPLC Column from the Prepared Filler

A stainless steel column of 25 cm in length and 0.46 cm in innerdiameter was filled with the filler made of silica gel supportingcellulose tris(4-chlorophenylcarbamate), which was prepared in step (3)above, by the slurry method. Then a separation column for opticalisomers was obtained.

Synthesizing Example 2 Preparation of an HPLC Column Containing a Fillerthat Includes 30 Weight % of Cellulose tris(4-chlorophenyl-carbamate)

(1) Surface Treatment of Silica Gel

The surface treatment was carried out in the same way as explained inSynthesizing Example 1 (1).

(2) Synthesis of Cellulose tris(4-chlorophenyl carbamate)

Cellulose tris(4-chlorophenyl carbamate) was synthesized in the same wayas explained in Synthesizing Example 1 (2).

(3) Preparation of a Filler Made of Silica Gel Supporting 30 Weight % ofCellulose tris(4-chlorophenyl carbamate)

150 g of cellulose tris(4-chlorophenyl carbamate) obtained in step (2)above was dissolved in 800 ml of acetone. 350 g of the treated silicagel prepared in step (1) above was uniformly coated with this polymersolution. The acetone was vacuum-distilled off from the coated silicagel at 40° C. for 30 minutes under 40 kPa. Then, the aimed filler madeof silica gel supporting 30 weight % of cellulose tris(4-chlorophenylcarbamate) was obtained.

(4) Preparation of a Filled HPLC Column from the Prepared Filler

A stainless steel column of 25 cm in length and 0.46 cm in innerdiameter was filled with the filler made of silica gel supportingcellulose tris(4-chlorophenylcarbamate), which was prepared in step (3)above, by the slurry method. Then a separation column for opticalisomers was obtained.

Synthesizing Example 3

Preparation of an HPLC Column Containing a Filler that Includes 20Weight % of Cellulose tris(4-chlorophenyl carbamate)

(1) Surface Treatment of Silica Gel

The surface treatment was carried out in the same way as explained inSynthesizing Example 1 (1).

(2) Synthesis of Cellulose tris(4-chlorophenyl carbamate)

Cellulose tris(4-chlorophenyl carbamate) was synthesized in the same wayas explained in Synthesizing Example 1 (2).

(3) Preparation of a Filler Made of Silica Gel Supporting 20 Weight % ofCellulose tris(4-chlorophenyl carbamate)

100 g of cellulose tris(4-chlorophenyl carbamate) obtained in step (2)above was dissolved in 600 ml of acetone. 400 g of the treated silicagel prepared in step (1) above was uniformly coated with this polymersolution. The acetone was vacuum-distilled off from the coated silicagel at 40° C. for 30 minutes under 40 kPa. Then, the aimed filler madeof silica gel supporting 20 weight % of cellulose tris(4-chlorophenylcarbamate) was obtained.

(4) Preparation of a Filled HPLC Column from the Prepared Filler

A stainless steel column of 25 cm in length and 0.46 cm in innerdiameter was filled with the filler made of silica gel supportingcellulose tris (4-chlorophenylcarbamate), which was prepared in step (3)above, by the slurry method. Then a separation column for opticalisomers was obtained.

Working Example 1 Measurement of the Capacity Factors and SimulatedMoving Bed Chromatographic Separation Using the Column and the FillerMade in Synthesizing Example 1

Ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxy-6-heptenoaterepresented by formula (I) was analyzed with the HPLC column made inSynthesizing Example 1, which HPLC column was fixed in a liquidchromatographic apparatus. The conditions of the analysis and thecapacity factors obtained are shown in Table 1. The chromatogram isshown in FIG. 3.

Eight (8) stainless steel columns, each being 1.0 cm in inner diameterand 10 cm in length, were filled by the slurry method with the fillerprepared in Synthesizing Example 1. The columns were fixed to asmall-sized simulated moving bed chromatographic separation apparatusand then separation was carried out. The operational conditions areshown below. The respective optical purities of the obtained raffinateand extract, and the productivity of the raffinate are shown in Table 2.

-   Mobile phase: n-hexane/2-propanol 68/32 (vol.) mixture-   Column temperature: 40° C.-   Supply rate of feedstock: 1.15 ml/min.-   Flow rate of raffinate: 2.97 ml/min.-   Flow rate of extract: 10.43 ml/min.-   Flow rate of eluent: 12.24 ml/min.-   Step time: 1.5 min.-   Concentration of feedstock: 20 mg/ml-mobile phase-   Flow rate in zone I: 14.40 ml/min.-   Flow rate in zone II: 3.97 ml/min.-   Flow rate in zone III: 5.13 ml/min.-   Flow rate in zone IV: 2.16 ml/min.

Working Example 2 Measurement of the Capacity Factors and SimulatedMoving Bed Chromatographic Separation Using the Column and the FillerMade in Synthesizing Example 2

Ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoaterepresented by formula (I) was analyzed with the HPLC column made inSynthesizing Example 2, which HPLC column was fixed in a liquidchromatographic apparatus. The conditions of the analysis and thecapacity factors obtained are shown in Table 1. The chromatogram isshown in FIG. 4.

Eight (8) stainless steel columns, each being 1.0 cm in inner diameterand 10 cm in length, were filled by the slurry method with the fillerprepared in Synthesizing Example 1. The columns were fixed to asmall-sized simulated moving bed chromatographic separation apparatusand then separation was carried out. The operational conditions areshown below. The respective optical purities of the obtained raffinateand extract, and the productivity of the raffinate are shown in Table 2.The chromatogram is shown in FIG. 4.

-   Mobile phase: n-hexane/2-propanol 68/32 (vol.) mixture-   Column temperature: 40° C.-   Supply rate of feedstock: 1.18 ml/min.-   Flow rate of raffinate: 4.59 ml/min.-   Flow rate of extract: 17.15 ml/min.-   Flow rate of eluent: 20.56 ml/min.-   Step time: 1.5 min.-   Concentration of feedstock: 20 mg/ml-mobile phase-   Flow rate in zone I: 23.58 ml/min.-   Flow rate in zone II: 6.43 ml/min.-   Flow rate in zone III: 7.61 ml/min.-   Flow rate in zone IV: 3.02 ml/min.

Comparative Example 1 Measurement of the Capacity Factors and SimulatedMoving Bed Chromatographic separation Using the Column and the FillerMade in Synthesizing Example 1

Ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoaterepresented by formula (I) was analyzed with the HPLC column made inSynthesizing Example 1, which HPLC column was fixed in a liquidchromatographic apparatus. The conditions of the analysis and thecapacity factors obtained are shown in Table 1. The chromatogram isshown in FIG. 5.

Eight (8) stainless steel columns, each being 1.0 cm in inner diameterand 10 cm in length, were filled by the slurry method with the fillerprepared in Synthesizing Example 1. The columns were fixed to asmall-sized simulated moving bed chromatographic separation apparatusand then separation was carried out. The operational conditions areshown below. The respective optical purities of the obtained raffinateand extract, and the productivity of the raffinate are shown in Table 2.

-   Mobile phase: n-hexane/2-propanol 55/45 (vol.) mixture-   Column temperature: 40° C.-   Supply rate of feedstock: 0.59 ml/min.-   Flow rate of raffinate: 1.90 ml/min.-   Flow rate of extract: 6.55 ml/min.-   Flow rate of eluent: 7.87 ml/min.-   Step time: 1.5 min.-   Concentration of feedstock: 20 mg/ml-mobile phase-   Flow rate in zone I: 9.43 ml/min.-   Flow rate in zone II: 2.88 ml/min.-   Flow rate in zone III: 3.46 ml/min.-   Flow rate in zone IV: 1.56 ml/min.

Comparative Example 2 Measurement of the Capacity Factors and SimulatedMoving Bed Chromatographic Separation Using the Column and the FillerMade in Synthesizing Example 2

Ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoaterepresented by formula (I) was analyzed with the HPLC column made inSynthesizing Example 2, which HPLC column was fixed in a liquidchromatographic apparatus. The conditions of the analysis and thecapacity factors obtained are shown in Table 1. The chromatogram isshown in FIG. 6.

As understood from FIG. 6, the separation of the enatiomers could not bedone under this condition.

Comparative Examples 3 Measurement of the Capacity Factors and SimulatedMoving Bed Chromatographic Separation Using the Column and the FillerMade in Synthesizing Example 3

Ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoaterepresented by formula (I) was analyzed with the HPLC column made inSynthesizing Example 3, which HPLC column was fixed in a liquidchromatographic apparatus. The conditions of the analysis and thecapacity factors obtained are shown in Table 1. The chromatogram isshown in FIG. 7.

Eight (8) stainless steel columns, each being 1.0 cm in inner diameterand 10 cm in length, were filled by the slurry method with the fillerprepared in Synthesizing Example 3. The columns were fixed to asmall-sized simulated moving bed chromatographic separation apparatusand then separation was carried out. The operational conditions areshown below. The respective optical purities of the obtained raffinateand extract, and the productivity of the raffinate are shown in Table 2.

-   Mobile phase: n-hexane/2-propanol 68/32 (vol.) mixture-   Column temperature: 40° C.-   Supply rate of feedstock: 1.05 ml/min.-   Flow rate of raffinate: 2.59 ml/min.-   Flow rate of extract: 9.32 ml/min.-   Flow rate of eluent: 10.86 ml/min.-   Step time: 1.5 min.-   Concentration of feedstock: 20 mg/ml-mobile phase-   Flow rate in zone I: 12.80 ml/min.-   Flow rate in zone II: 3.48 ml/min.-   Flow rate in zone III: 4.53 ml/min.

Flow rate in zone IV: 1.94 ml/min. TABLE 1 Amount of Conditions the ofk1′ Column supported analysis k2′ Chromatogram W. Ex. 1 Made in 24 wt %(1)* 1.06 S.E. 1 1.49 W. Ex. 2 Made in 30 wt % (1)* 1.74 S.E. 2 2.36 C.Ex. 1 Made in 24 wt % (2)* 0.51 S.E. 1 0.68 C. Ex. 2 Made in 30 wt %(3)* 0.88 S.E. 2 — C. Ex. 3 Made in 20 wt % (1)* 0.91 FIG., 7 S.E. 31.26*The conditions of the analyses(1) Mobile phase: n-hexane/2-propanol 68/32 (vol.) mixture, Flow rate:1.0 ml/min., Temperature: 40° C., Detection: 254 nm, Injection amount:1.5 mg/ml(mobile phase) × 2.5 μl(2) Mobile phase: n-hexane/2-propanol 55/45 (vol.) mixture, Flow rate:0.5 ml/min., Temperature: 40° C., Detection: 254 nm, Injection amount:1.5 mg/ml(mobile phase) × 2.5 μl(3) Mobile phase: n-hexane/2-propanol 55/45 (vol.) mixture, Flow rate:1.0 ml/min., Temperature: 40° C., Detection: 254 nm, Injection amount:1.5 mg/ml(mobile phase) × 2.5 μlThe value of k′ was calculated by the following formula:k′=(v−v0)/v0

wherein v0 is the retention volume of tri-tert-benzyl benzene, v is theretention volume of the solute. TABLE 2 W. Ex. 1 W. Ex. 2 C. Ex. 1 C.Ex. 2 C. Ex. 3 Mobile phase (1) (1) (2) (2) (1) Optical purity of 99.599.4 — —*2 99.5 raffinate (% ee) Optical purity of 94.7 94.8 — —*2 94.6extract (% ee) Productivity 0.88 0.90 0.45 —*2 0.80 (kg-rac./kg-CSP/day)*1The mobile phases(1) n-hexane/2-propanol 68/32 (vol.) mixture(2) n-hexane/2-propanol 55/45 (vol.) mixture*1The weight (kg) of a racemic compound that can be separated with 1 kgof the filler per day.*2Because the mixture was not separated in the liquid chromatographicapparatus using the single column, the production with the small-sizedsimulated moving bed chromatographic apparatus was not carried out.Industrial Applicability

This invention provides a process for continuously and efficientlyisolating ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-hepteno-ate by a simulated moving bed chromatographic separation utilizing afiller having an excellent optical resolution ability. This process cansubstantially reduce the industrial production cost.

1. A process for producing optically active ethyl (3R, 5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoatewhich comprises separating an optical isomer mixture of ethyl7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoateby a simulated moving bed chromatography employing a filler for liquidchromatography comprising a carrier and a cellulose tris(4-chlorophenylcarbamate) supported on the carrier wherein the amount of the cellulosetris(4-chlorophenyl carbamate) is at least 23 weight % based on thetotal weight of the carrier and the cellulosetris(4-chlorophenylcarbamate) under the condition that capacity factorsk1′ and/or k2′ is at least 1, the capacity factors being calculated bythe following formulae:k1′=(v1−v0)/v0, andk2′=(v2−v0)/v0 wherein v1 and v2 each are the respective retentionvolumes of the optical isomers, which are the solutes, and v0 is thedead volume.
 2. The process as claimed in claim 1, wherein the cellulosetris(4-chlorophenyl carbamate) has a number average polymerizationdegree of at least
 5. 3. The process as claimed in claim 1, wherein thedegree of substitution with 4-chlorophenyl carbamate groups in thecellulose tris(4-chlorophenyl carbamate) is 10%-100%.
 4. The process asclaimed in claim 1, wherein the carrier is a porous inorganic substance.5. The process as claimed in claim 1, wherein the carrier is silica gel.